In this Halloween season, the sight of a plastic pig's snoutcovering a small human face excites no undue notice. Itcomes with the trick-or-treat territory.
However, a biotechnology company is masking pig cellswith mouse antibodies. Its trick-and-treat strategy aims tofake out a human patient's brain cells into acceptingtreatment by immunologically disguised porcine neurons.
Diacrin Inc., of Charlestown, Mass., is developingproprietary populations of transplantable porcine cells totreat intractable diseases, such as Parkinson's,Huntington's and Alzheimer's. The firm's director of celltransplantation research, cell biologist JonathanDinsmore, is co-author of a paper in the NovemberNature Medicine titled "Transplanted xenogeneic neuralcells in neurodegenerative disease models exhibitremarkable axonal target specificity and distinct growthpatterns of glial and axonal fibres."
Since a bold Mexican surgeon transplanted human cellsinto the brains of Parkinson patients in 1987, theexperimental but apparently beneficial practice has spreadin Europe and the U.S. (See BioWorld Today, June 2,1995, p. 1.) But _ and it's a big but _ human fetaltissues (the preferred cell source) are hard to come by,and widely frowned upon, as replacement parts for thewasting dopaminergic brain cells of Parkinson's diseasepatients.
Embryonic swine could fill that demand, Dinsmore toldBioWorld Today, given "the development ofimmunoprotection methodology, which prevents rejectionof the cells." He is co-inventor of several pending patentson immunomodulation of porcine fetal brain cells, toadapt them for transplantation into humans. Diacrin isexclusive licensee of an issued U.S. patent fromMassachusetts General Hospital.
Dinsmore's main co-inventor, and first author of theNature Medicine paper, is neuroscientist Ole Isacson, ofHarvard Medical School.
200,000 Pig Cells Replenish Lost Neurons
"At Diacrin," Dinsmore explained, "we're experts on theisolation and characterization of the pig cells. The groupsat Harvard and the Lahey Clinic are experts at doing thexenotransplantation and analysis of graft function."
The Nature Medicine paper reports experiments in 50 ratsturned into Parkinson's or Huntington's disease modelsby ablation of neurons in one cerebral hemisphere. EachParkinson's animal received 200,000 fetal pig cells,delivered by needle through the skull precisely to a bulls-eye target two cubic millimeters in size within the brain'sdopamine-producing corpus striatum. In humans, thetarget area is about one cubic centimeter.
Dinsmore observed that "In Parkinson's, one needs tolose about 90 percent of one's dopamine neurons beforebeginning to exhibit symptoms of the disease. We'retrying to put back, not the total complement, but a smallerpercentage, to bring them up into the functional rangeagain.
"We have several species-specific markers," Dinsmorecontinued, "which enable us to follow the xenografted pigcells. We were looking to see, at the structural level, ifthere was a correct pattern of outgrowth from these graftsto the appropriate targets in the rat brains. That in fact iswhat we found."
This meant confirmation that the fast-growing fetal cells,born to send out neuronal projections into their owndeveloping brain, found their proper targets in the adultrat brains instead. Moreover, Dinsmore pointed out, theexperiment showed that "it works across species, so thatyou can take cells from one kind of animal, put them inanother, and they still recognize the appropriate signals."
Rats that model Parkinson's do so by constant circling inthe direction of their unilateral brain lesion. This trait ismeasurable to assess the efficacy of experimentaltherapies. "The transplant of those pig cells," Dinsmoresaid, "do indeed correct that behavioral deficit, although,"he added, "this is not addressed in the currentpublication."
Nor are Diacrin's in vivo safety studies of its immuno-camouflaged pig cells on subhuman primates,cynomolgus and rhesus monkeys, which too, he said, willbe published in the future.
The successful animal trials, on Huntington's as well asParkinson's models, prompted the FDA to authorizePhase I clinical trials of Diacrin's porcine cells in bothParkinson's and Huntington's patients.
Parkinson's Patients Get Porcine Neuron Graft
Between April and September of this year, the Harvardgroup has administered non-immuno-masked porcinecells to four Parkinson's patients, three men and onewoman, in their late 50s and early 60s. All receivedcyclosporine, the standard immunosuppressive drug, toward off graft rejection.
But early last month, Dinsmore, said, "the first patientreceived porcine cells treated with our patentedimmunoprotective technique."
That method, he explained, "is to use a fragment of anantibody directed against the MHC I [majorhistocompatibility class I] antigen on the surface of donorporcine cells. MHC is a major determinant for cellrejection. By pretreating the cells with this antibodyfragment directed against porcine class I, we've been ableto inhibit rejection. It interferes with normal recognitionof the donor xenograft cells by recipient T cells."
He added, "From experiments we've done, this inductionof immune tolerance appears to be permanent."
The ongoing Phase I trial, Dinsmore observed, "is clearlya safety study. However, if we do get sufficient efficacydata, then we would use that to our advantage."
He concluded, "Pending publication of specific datareporting on the degree of improvement in all theserecipient patients, I think we can say they look to begetting better." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.